This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The diagnosis of disease today is overwhelmingly based upon anatomy, whereas systemic factors such as energy production are not emphasized and are generally ignored in diagnosis. Disruption of normal cellular energy metabolism via mitochondrial defects has been linked to some well-known diseases such as diabetes mellitus, neonatal hemochromatosis, and a variety of cancers. Metabolic syndrome is a cluster of interrelated symptoms such as insulin resistance, obesity, dyslipidemia (disorder in lipoprotein metabolism), and hypertension, that has no one clear mechanism of action. However, metabolic syndrome may have its origins in mitochondrial defects. Our long-term project goal is to link mutations in mitochondrial DNA (mtDNA) with the predisposition and expression of metabolic syndrome. Because of the systemic importance of the mitochondria and the variability in the phenotypes seen for each mutation, it is clear that no one set of diagnostic criteria can currently define mitochondrial disease. Diseases that are currently viewed as idopathy (due to unknown causes, such as metabolic syndrome) may eventually be shown to be caused by mitochondrial defects. For this purpose, we further propose to use mtDNA analyses to develop two non-invasive screening tests for diabetes milletus and metabolic syndrome: Diffuse Optical Spectroscopy (DOS) and Micro-Organic Breath Analysis (MOBA).